Background: The phase 3 POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the R-CHOP regimen for large B-cell lymphomas. However, it is unknown if Pola can be safely incorporated into intensified regimens typically utilized for the highest risk histologies. To address this question, we conducted a prospective trial (NCT04231877) evaluating Pola with dose adjusted etoposide, cyclophosphamide, doxorubicin, and rituximab (Pola-DA-EPCH-R). Methods: This is a single center, open label, investigator-initiated clinical trial of 6 cycles of Pola-DA-EPCH-R in aggressive large B-cell lymphomas where DA-EPOCH-R is considered standard (eg. HGBCL, PMBCL, and select DLBCL-NOS). Pola is given at 1.8 mg/kg on day 1 without intra-patient dose escalation. All other components of the regimen including escalation of chemotherapy dosing based on neutrophil and platelet nadirs from the previous cycle are given according to Dunleavy et al NEJM 2013. The primary objective is to estimate the safety of Pola-DA-EPCH-R as measured by the rate of dose-limiting toxicities (DLTs) in the first 2 cycles with pre-specified suspension rules if the lower limit of an 80% confidence interval cannot exclude a DLT rate of > 20%. Efficacy, survival, and correlative analyses will also be performed. Results: 18 patients enrolled on study and as of Feb 15, 2022, 3 patients remain on study treatment. Median age was 64 years (range 41-74). With only 3 DLTs, the study met its primary endpoint for safety. Five SAEs were observed, including one grade 5 sepsis/typhlitis (during cycle 1), 3 episodes of febrile neutropenia, and a grade 3 perforation of a colonic diverticula which required a treatment delay of 12 days before completing all expected study therapy. Other grade 3+ non-heme AEs in more than one pt. include hyperglycemia (17%), oral mucositis (17%), incidental asymptomatic pulmonary embolism (17%), abdominal pain (11%), and hypokalemia (11%). Grade 1 peripheral sensory neuropathy was uncommon (22%), no grade 2+ neuropathy was observed. One patient required a decrease in Pola dosing due to a platelet nadir at dose level 1. Among those with at least 2 cycles of treatment, 94% were able to increase chemotherapy to at least dose level 2 (Table). Post cycle 2 interim overall response rate (ORR) and complete response (CR) rate was 88% and 24%, respectively. EOT ORR and CR was 93% and 71%, respectively, with one PD. Updated data will be presented at the meeting. Conclusions: Using Pola at 1.8 mg/kg to replace vincristine in the DA-EPOCH-R regimen appears feasible and met its primary safety endpoint. These data support the further evaluation and use of this approach in histologies where the potential benefit of both an intensified regimen and Pola may be desired. Clinical trial information: NCT04231877.